Systemic connective tissue diseases : SYSTEMIC SCLEROSIS
Systemic sclerosis (SSc) is a chronic multisystem disorder of unknown etiology characterized clinically by thickening of the skin caused by accumulation of connective tissue and by involvement of visceral organs, including the gastrointestinal tract, lungs, heart, and kidneys.
Etiology
Immunologic mechanisms and heredity (certain HLA subtypes) play a role in etiology. SSc-like syndromes can result from exposure to vinyl chloride, bleomycin, pentazocine, aromatic hydrocarbons, contaminated rapeseed oil, or l-tryptophan.
Pathogenesis
IMMUNOLOGIC ABNORMALITIES:Patients with scleroderma exhibit abnormalities of the humoral and cellular immune systems. The number of circulating Вlymphocytes is normal, but there is evidence of hyperactivity, as manifested by hypergammaglobulinemia and cryoglobulinemia. Antinuclear antibodies are common but are usually in a lower titer than in SLE. Antibodies virtually specific for scleroderma include nucleolar autoantibodies, antibodies to ScL-
Classification
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Classification of Scleroderma |
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Localized Scleroderma (Localized cutaneous fibrosis) |
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Systemic Scleroderma (Cutaneous and noncutaneous involvement) |
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CLINICAL MANIFESTATIONS
Skin
In the skin, a thin epidermis overlies compact bundles of collagen that lie parallel to the epidermis. Fingerlike projections of collagen extend from the dermis into the subcutaneous tissue and bind the skin to the underlying tissue. Dermal appendages are atrophied, and rete pegs are lost. In early stages of disease, a mononuclear cell infiltrate of predominantly T cells surrounds small dermal blood vessels. Increased numbers of T cells, monocytes, plasma cells, and mast cells are found, particularly in the lower dermis of involved skin.
Gastrointestinal Tract
In the lower two-thirds of the esophagus, the histologic findings consist of a thin mucosa and increased collagen in the lamina propria, submucosa, and serosa. The degree of fibrosis is less than in the skin. Atrophy of the muscularis in the esophagus and throughout the involved portions of the gastrointestinal tract is more prominent than the amount of fibrotic replacement of muscle. Ulceration of the mucosa is often present and may be due to either SSc or superimposed peptic esophagitis. Chronic esophageal reflux can lead to metaplasia of the lower esophagus (Barrett’s esophagus), which is a premalignant lesion.
Lung
With pulmonary involvement, diffuse interstitial fibrosis, thickening of the alveolar membrane, and peribronchial and pleural fibrosis are observed. Bronchiolar epithelial proliferation accompanies the pulmonary fibrosis. Rupture of septa produces small cysts and areas of bullous emphysema. Small pulmonary arteries and arterioles show intimal thickening, fragmentation of the elastica, and muscular hypertrophy; this may occur without interstitial pulmonary fibrosis and produce pulmonary hypertension, particularly in a subset of patients with limited cutaneous SSc.
Musculoskeletal System
The synovium in patients with arthritis is similar to that seen in early rheumatoid arthritis and shows edema with infiltration of lymphocytes and plasma cells. A characteristic finding is a thick layer of fibrin overlying and within the synovium. Later in the disease the synovium may become fibrotic. Fibrinous deposits appear on the surfaces of tendon sheaths and in the overlying fascia and may lead to audible creaking over moving tendons.
Heart
Cardiac involvement consists of degeneration of myocardial fibers and irregular areas of interstitial fibrosis that are most prominent around blood vessels. Intermittent spasm of blood vessels may result in contraction band necrosis, similar to change observed in myocardial infarction in patients with atherosclerotic coronary artery disease. Fibrosis also involves the conduction system, leading to atrioventricular conduction defects and arrhythmias. The wall of smaller coronary arteries may be thickened. Fibrinous pericarditis and pericardial effusions are found in some patients.
Kidney
Renal involvement is found in over half the patients and consists of intimal hyperplasia of the interlobular arteries; fibrinoid necrosis of the afferent arterioles, including the glomerular tuft; and thickening of the glomerular basement membrane. Small cortical infarctions and glomerulosclerosis may be present. The renal pathologic change is often indistinguishable from that observed in malignant hypertension. Renal vascular lesions, however, may be present in the absence of hypertension. Immunofluorescence studies of kidney have shown IgM, complement components, and fibrinogen in the walls of affected vessels. Angiographic renal studies in patients with SSc may show constriction of the intralobular arteries, a finding that simulates the vasospasm of the digital arteries observed in Raynaud’s phenomenon. Cold-induced Raynaud’s phenomenon has been shown to decrease renal blood flow.
Therearetwomajorformsofscleroderma, localizedsclerodermaandsystemicscleroderma (sclerosis). Diffuse (dcSSc) andlimited (lcSSc) sclerodermaarethetwomaintypesofsystemicsclerosis.
Localized Scleroderma
The more common form of the disease, localized scleroderma, only affects the skin without any internal organ involvement. It often appears in the form of waxy patches (morphea) or streaks on the skin (linear scleroderma).
Vascular abnormalities, especially of the microvasculature are a prominent feature of SSc.
One subset is referred to as diffuse cutaneous scleroderma and is characterized by the rapid development of symmetric skin thickening of proximal and distal extremities,
These criteria are not, however, applicable to clinical practice as many patients have SSc who do not meet these criteria. Scleroderma can also occur in a localized form limited to the skin, subcutaneous tissue, and muscle and without systemic involvement. Localized scleroderma occurs most often in children and young women but can affect any age group. The two localized forms are morphea, which occurs as single or multiple plaques of skin induration, and linear scleroderma, which involves an extremity or face. Linear scleroderma of one side of the forehead and scalp produces a disfiguration referred to as en coup de sabre because it resembles a wound from a sword. It may be associated with hemiatrophy of the same side of the face.
SSc also occurs in association with features of other connective tissue diseases. The term overlap syndrome has been used to describe such patients. Undifferentiated connective tissue disease has been suggested as a designation for patients who do not have diagnostic criteria for any one connective tissue disease.
Clinical manifestations of scleroderma.A, Generalized morphea.B, Diffuse edema of hands. C, Firm, thickened skin. D, Flexion contractures of fingers.E, Raynaud’s phenomenon (pallor phase).
It is not uncommon for this less severe form of scleroderma to regress or stop progressing without treatment.
Systemic Scleroderma
Systemicsclerodermaalwaysleadstosomeinternalorganinvolvement. Itisfurtherdividedintotwosubsetsofdisease, limitedordiffuse. AccordingtoLeRoyandcolleagues, limitedordiffusediseaseisbasedontheextentofskintightening.1Inlimiteddisease (formerlycalled CREST
CREST syndrome– skintighteningisconfinedtothefingers, hands, andforearmsdistaltotheelbows, withorwithouttighteningofskinofthefeetandofthelegsdistaltotheknees. Proximalextremitiesandthetrunkarenotinvolved. Indiffusediseaseordiffusecutaneoussystemicsclerosis (dcSSc), theskinoftheproximalextremitiesandtrunkisalsoinvolved. BothdcSScandlcSScareassociatedwithinternalorganinvolvement;however, patientswithdcSScareatgreaterriskforclinicallysignificantmajororgandysfunction. Systemicsclerosissinescleroderma (ssSSc) is a raredisorderinwhichpatientsdevelopvascularandfibroticdamagetointernalorgans (phenotypicallysimilartothatinlimitedscleroderma), intheabsenceofcutaneoussclerosis.
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Subsets of Systemic Sclerosis |
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Diffuse Cutaneous Systemic Sclerosis (dcSSc) |
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· Onset of Raynaud‘s within 1 year of onset of skin changes (puffy or hidebound) · Truncalandacralskininvolvement · Presenceoftendonfrictionrubs · Early and significant incidence of interstitial lung disease, oliguric renal failure, diffuse gastrointestinal disease, and myocardial involvement · Absenceofanticentromereantibodies · Nailfold capillary dilation and capillary destruction · Antitopoisomeraseantibodies (30% ofpatients) |
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Limited Cutaneous Systemic Sclerosis (LcSSc) |
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· Raynaud’s phenomenon for years (occasionally decades) · Skin involvement limited to hands, face, feet, and forearms (acral) or absent · A significant late incidence of pulmonary hypertension, with or without interstitial lung disease, trigeminal neuralgia, skin calcifications, telangiectasias · A high incidence of anticentromere antibodies (70%-80%) · Dilated nailfold capillary loops, usually without capillary dropout |
Raynaud’s PhenomenonSSc usually begins insidiously; the first symptoms are frequently Raynaud’s phenomenon and puffy fingers. Some 95% of patients will experience Raynaud’s phenomenon, which is defined as episodic vasoconstriction of small arteries and arterioles of fingers, toes, and sometimes the tip of the nose and earlobes. Episodes are brought on by cold exposure, vibration, or emotional stress. Patients experience pallor and/or cyanosis followed by rubor on rewarming. Pallor and/or cyanosis are usually associated with coldness and numbness of fingers and/or toes, and rubor with pain and tingling. Not all patients appreciate the three color phases.
Skin Features
In early disease, fingers and hands are swollen. Swelling may also involve forearms, feet, lower legs, and face. However, lower extremities are relatively spared. This edematous phase may last for a few weeks, months, or even longer. The edema may be pitting or nonpitting and accompanied by erythema. The skin changes begin distally in the extremities and advance proximally. The skin gradually becomes firm, thickened, and eventually tightly bound to underlying subcutaneous tissue (indurative phase). In patients with diffuse cutaneous scleroderma, skin changes will become generalized, involving initially the extremities, followed by the face and trunk over a period of time, varying from months to a few years. In some patients, the skin changes may develop gradually over several years. Rapid progression of these changes over a 1- to 3-year period is associated with a greater risk of visceral disease, particularly of the lungs, heart, or kidneys.
The overlying skin may break down, with drainage of calcific material. Involvement of the face results in thinning of the lips, loss of skin wrinkles and facial expression, as well as microstomia, which may make eating and dental hygiene difficult. The nose takes on a pinched or beaklike appearance. Wrinkles appear around the mouth perpendicular to the lips. Small telangiectatic mats may appear on the fingers, face, lips, tongue, and buccal mucosa after several years. They are seen more frequently in patients with limited cutaneous SSc but are also observed in patients with long-standing diffuse cutaneous SSc. The capillary beds of nail folds of the fingers may show enlargement of capillaries with little or no capillary loss, usually indicative of limited cutaneous scleroderma. In diffuse cutaneous scleroderma, there is disorganization of the capillary beds with dilated capillaries interspersed with areas where capillaries have disappeared. These capillary changes, which are observed by wide-angle microscopy or with an ophthalmoscope used as a magnifier, are not found in patients who have only Raynaud’s phenomenon.
Musculoskeletal Features
More than half the patients with SSc complain of pain, swelling, and stiffness of the fingers and knees. A symmetric polyarthritis resembling rheumatoid arthritis may be seen. In more advanced stages of the disease, leathery crepitation can be palpated over moving joints, especially the knee. Extensive fibrotic thickening of the tendon sheaths in the wrist can produce a carpal tunnel syndrome. Muscle weakness is usually present in patients with severe skin involvement and, in most cases, is due to disuse atrophy. There is a distinctive histologic myopathy that accompanies SSc that is not associated with muscle enzyme abnormalities. A few patients develop a myositis characterized by proximal muscle weakness and muscle enzyme elevations that are identical to polymyositis (overlap syndrome). In addition to terminal phalanges, resorption of bone may involve ribs, clavicle, and angle of mandible.
The majority of patients from both subsets of SSc have gastrointestinal involvement. Symptoms attributable to esophageal involvement are present in >50% of patients and include epigastric fullness, burning pain in the epigastric or retrosternal regions, and regurgitation of gastric contents. These symptoms, most noticeable when the patient is lying flat or bending over, are due to the reduced tone of the gastroesophageal sphincter and to dilatation of the distal esophagus. Peptic esophagitis frequently occurs and may lead to strictures and narrowing of the lower esophagus. However, it seldom results in bleeding. Barrett’s metaplasia may develop, but transition to adenocarcinoma is uncommon. Dysphagia, particularly of solid foods, may occur independent of other esophageal symptoms and is caused by loss of esophageal motility due to neuromuscular dysfunction.
Hypomotility of the small intestine produces symptoms of bloating and abdominal pain and may suggest an intestinal obstruction or paralytic ileus (pseudoobstruction). Malabsorption syndrome with weight loss, diarrhea, and anemia is due to bacterial overgrowth in the atonic intestine or possibly to obliteration of lymphatics by fibrosis. Roentgenographic features of the second and third portions of the duodenum and of the jejunum include dilatation, loss of the usual feathery pattern, and delayed disappearance of barium. Pneumatosisintestinalis occasionally occurs and appears as radiolucent cysts or linear streaks within the wall of the small intestine. Benign pneumoperitoneum may result from the rupture of these cysts. Involvement of the large intestine may cause chronic constipation and fecal impaction with episodes of bowel obstruction. Pulmonary
Features Pulmonary involvement occurs in at least two-thirds of SSc patients and is now the leading cause of death in SSc, replacing renal disease, which can usually be treated effectively. The most common symptom is exertionaldyspnea, often accompanied by a dry, nonproductive cough. Bilateral basilar rales may be present. In the majority of patients, symptoms usually correlate with radiologic evidence of pulmonary fibrosis and with restrictive lung disease on pulmonary function tests.
Interstitial pulmonary fibrosis may be the predominant lesion in patients with diffuse or limited cutaneous SSc. Patients with diffuse cutaneous involvement who have antitopoisomerase 1 antibodies are particularly at risk of developing severe pulmonary fibrosis. In the absence of significant interstitial fibrosis, a severe form of pulmonary arterial hypertension may develop after many years of disease in a subset of patients with limited cutaneous SSc. Fewer than 10% of patients will develop this complication, which is caused by narrowing and obliteration of pulmonary arteries and arterioles by intimal fibrosis and medial hypertrophy. Pulmonary hypertension is manifested initially by exertionaldyspnea and eventually by the appearance of right-sided heart failure. Pulmonary artery pressure can be measured noninvasively by two-dimensional echocardiography. The prognosis is extremely poor with the development of pulmonary hypertension; the mean duration of survival is approximately 2 years.
Cardiac Features
Primary cardiac involvement in SSc includes pericarditis with or without effusions, heart failure, and varying degrees of heart block or arrhythmias. The majority of patients with diffuse cutaneous SSc have cardiac abnormalities. Cardiomyopathy attributable to myocardial fibrosis appears in <10% of patients and involves primarily those patients with diffuse cutaneous scleroderma. Radionuclide studies have shown abnormalities of left ventricular function due to myocardial fibrosis. Cold-induced vasospasm of the hands produces defects in myocardial thallium perfusion. The characteristic pathologic feature of contraction band necrosis results from cardiac muscle damage caused by intermittent vasospasm of coronary vessels. Patients may experience angina pectoris even though coronary angiograms are normal. Patients can also develop left ventricular failure secondary to systemic hypertension or corpulmonale secondary to pulmonary arterial hypertension.
Renal Features
Renal failure was the leading cause of death in SSc until the advent of effective treatment. Significant renal disease occurs mostly in those patients with diffuse cutaneous scleroderma. A high risk of renal crisis is present in those patients who have rapidly progressive widespread skin thickening in their first 2 to 3 years of disease. Renal crisis is characterized by malignant hypertension, which can progress rapidly to renal failure. These patients manifest hypertensive encephalopathy, severe headache, retinopathy, seizures, and left ventricular failure. Hematuria and proteinuria are followed by oliguria and renal failure. The mechanism for the hypertensive crisis is activation of the renin-angiotensin system
The 1980 Criteria for systemic sclerosis (ACR)
Major criterion:
Proximal scleroderma: symmetric thickening, tightening, and induration of the skin of the fingers and/or the skin proximal to the metacarpophalangeal or metatarsophalangeal joints. The changes may affect the entire extremity, face, neck, and trunk (thorax and abdomen).
Minor criteria:
1. Sclerodactyly: preceding skin changes limited to the finger.
2. Digital pitting scars or loss of substance from the finger pad: depressed areas at tips of fingers or loss of digital pad tissue as a result of ischemia.
3. Bibasilar pulmonary fibrosis: bilateral reticular pattern of linear or lineonodular densities most pronounced in basilar portions of the lungs on standard chest roentgenogram; may assume appearance of diffuse mottlng or “honeycomb lung”. These changes should not be attributable to primary lung disease.
*Thepatientshouldfulfillthemajorcriterionortwoofthethreeminorcriteria.
LABORATORY FINDINGS
The erythrocyte sedimentation rate may be elevated. Hypoproliferativeanemia related to chronic inflammation is the most common cause of anemia in SSc. Anemia may also be caused by iron deficiency secondary to gastrointestinal bleeding. Bacterial overgrowth due to atony of the small bowel may lead to vitamin B12 and/or folic acid-deficiency anemia. Microangiopathichemolyticanemia is most often associated with renal involvement and is caused by the presence of intravascular fibrin in renal arterioles. Polyclonal hypergammaglobulinemia, consisting mostly of IgG, is found in approximately half the patients. Rheumatoid factor, in low titer, is present in 25% of patients. Cryoglobulins may be present in the serum. Antinuclear antibodies detected by using a cultured human laryngeal carcinoma cell line (HEp-2) substrate are present in 95% of patients.
Antinuclear antibodies that have a high specificity for SSc are antitopoisomerase 1 (Scl-70), antinucleolar, and anticentromere. Antitopoisomerase 1, originally called anti-Scl-70, recognizes the nuclear enzyme DNA topoisomerase
Laboratory Studies
The following findings may be found with laboratory studies:
- Increased erythrocyte sedimentation rate
- Thrombocytopenia
- Hypergammaglobulinemia
- Microangiopathic hemolytic anemia
- Increased creatine phosphokinase levels in patients with muscle involvement
- Increased urea and creatinine levels in patients with kidney involvement
- C-reactive protein: The nonspecific inflammatory marker C-reactive protein was found elevated in about one quarter of patients with systemic sclerosis, especially early disease, in whom it correlated with disease activity, severity, poor pulmonary function, and shorter survival.
Imaging Studies
Chest radiographs may show normal findings in 5-10% of the patients, even when the patients have respiratory tract symptoms. In approximately 30-60% of patients, fibrosis of the basal parts of the lungs is observed. Occasionally, pictures of diffuse ground-glass and honeycomb lung patterns are observed. In patients with honeycomb lung patterns, changes are irreversible. These changes can be an important feature of patient’s response to treatment.
Bone radiography reveals generalized osteopenia, which most commonly affects the hands. Intra-articular calcifications often are observed.
Scintigraphy of the esophagus may reveal a disturbance of the esophageal passage.
Manometric esophageal changes may be observed during invasive examination.
Cardiac and pulmonary vascular involvement in systemic sclerosis should be evaluated. Cardiac abnormalities may be assessed by Doppler echocardiography.Left– and right-sided heart diseases were found to be common in persons with systemic sclerosis. A few patients had a restrictive mitral flow pattern, possibly due to primary cardiac involvement of systemic sclerosis.
Because cardiac involvement is one of the major problems in systemic sclerosis, evaluation of ventricular function using echocardiographic strain imaging should be considered, because it appears to be useful to detect subclinical cardiac involvement in systemic sclerosis patients with normal standard echocardiographic and tissue Doppler velocity findings.
Antihistone antibodies can be observed in the course of systemic sclerosis, but they are not characteristic. The following antinuclear antibodies (ANAs) are characteristic of scleroderma:
- Antibodies against topoisomerase I DNA (Scl 70) are detected in the serum of patients with systemic sclerosis. The antibodies are detected in two thirds of patients with dSSc and interstitial lung fibrosis.
- Anticentromere antibodies (ACAs) are most commonly detected in patients with lSSc; in these patients, changes in the heart, kidneys, and lungs (without fibrosis) are observed less frequently than in other patients.
ANAs can be detected in the course of systemic sclerosis. ANAs include antibodies against fibrillarin, a 34-kd protein of ribonucleoprotein U3 RNP; antibodies against the ribonucleoproteinnucleolar 7-2 RNA protein particle Th RNP; and antibodies to 20-110-kd proteins related to preribosomes (PM-Scl). Anti-PM/Scl antibodies are seen in roughly 24% of patients with polymyositis/systemic sclerosis overlap syndrome. They are also found in 3-10% of systemic sclerosis patients.The spectrum of systemic sclerosis-associated ANA differs in patients with and without cutaneous involvement.
Elevated high-sensitivity C-reactive protein appears related to the occurrence of antimitochondrial antibody in these patients.
With capillary microscopy, enlarged capillaries are observed in all 3 portions of the capillary nail fold–arterial, apical, and venous– and especially at the edge of the nail fold. Adjacent areas are avascular.
Spirometry demonstrates functional lung disturbances. In approximately 70% of patients, the DLCO is decreased.
Histologic Findings
In the active indurative phase, a loss of rete ridges occurs, epidermal skin appendages atrophy, and collagen fibers in the reticular dermis appear broad and hyalinized. A loss of space between collagen bundles is noted. Mononuclear cells, mostly T cells, form a variable perivascular infiltrate in the deep dermis and subcutis. Later, sclerotic changes predominate. The number of adnexal structures is reduced, and a loss of periadnexal fat is noted.
The amount of hyalinized collagen, myofibroblasts, mean epidermal thickness, the mononuclear cellular infiltration, and the frequency of focal exocytosis varied significantly between those with and those without local clinical skin involvement.
TREATMENT
EULAR recommendations:
I. SSc-related digital vasculopathy (Raynaud’s phenomenon, digital ulcers).
1. Nifedipineand intravenous iloprost reduce the frequency and severity ofSSc-related Raynaud’s phenomenon (SSc-RP) attacks.Dihydropiridine-type calcium antagonists, usually oral nifedipine,should be considered for first-line therapy for SSc-RP,and intravenous iloprost, or other available intravenousprostanoids, should be considered for severe SSc-RP.Intravenous prostanoids (in particular iloprost) should be considered in the treatment of active digital ulcers in patients with SSc. Intravenous iloprost (0.5–2 ng/kg per minute for 3–5 consecutive days) significantly reduced the number of digital ulcers in comparison with placebo in one small RCT.
2. Bosentan should be considered in diffuse SSc with multiple digital ulcers, after failure of calcium antagonists and, usually, prostanoid therapy.
II. SSc-PAH
Two high-quality RCT indicate that bosentan improvesexercise capacity, functional class and some haemodynamicmeasures in pulmonary arterial hypertension (PAH). Bosentanshould be strongly considered to treat SSc-PAH.Sildenafil (a selective type 5 phosphodiesterase inhibitor), may be considered to treat SSc-PAH(orally at a dose of 20 mg, 40 mg or 80 mg three times a day).
III. SSc-related skin involvement
Methotrexate may be considered for treatment of skinmanifestations of early diffuse SSc.
IV. Scleroderma interstitial lung disease
In view of the results from two high-quality RCT and despiteits known toxicity, cyclophosphamide should be considered forthe treatment of SSc-related interstitial lung disease (SSc-ILD).The efficacy and safety of cyclophosphamide in the treatmentof SSc-ILD was evaluated in two high. The first trial, involving 158 SSc patients with activealveolitis, demonstrated that cyclophosphamide given orally at
a dose of 1–2 mg/kg per day improved lung function tests,dyspnoea score and quality of life over 12 months compared.
V. Scleroderma renal crisis
Despite the lack of RCT, experts believe that angiotensinconvertingenzyme (ACE) inhibitors should be used in thetreatment of scleroderma renal crisis (SRC).
RCT evaluating the efficacy of ACE inhibitors in thetreatment of SRC are lacking. Since the first report demonstratinga beneficial effect of ACE inhibitors in two patients withSRC,64 numerous case reports and uncontrolled studies havereported on ACE inhibitors in SRC. A prospective analysis of108 patients with SRC has suggested that patients on ACEinhibitors (captopril in 47 and enalapril in eight) had asignificantly better survival rate at 1 year (76%) and 5 years(66%) compared with patients not on ACE inhibitors (15% at1 year and 10% at 5 years, respectively). Treatment with ACEinhibitors was significantly associated with better survival in
SRC, after adjustment for age and blood pressure (p,0.001).
VI. SSc-related gastrointestinal disease
Despite the lack of specific RCT, experts believe that protonpump inhibitors (PPI) should be used for the prevention of SScrelatedgastro-oesophageal reflux disease (GORD), oesophagealulcers and strictures.Specific RCT for the efficacy of PPI in patients with SSc arelacking. The efficacy of PPI in the treatment of GORD in ageneral population is well documented in meta-analyses ofRCT.
